1. Field Of The Invention
The invention relates generally to growth factors and specifically to a novel member of the fibroblast growth factor family, denoted fibroblast growth factor homologous factor-2 (FHF-2) and the polynucleotide encoding FHF-2.
2. Description Of Related Art
The fibroblast growth factor family encompasses a group of structurally related proteins with a wide range of growth promoting, survival, and/or differentiation activities in vivo and in vitro (reviewed in Baird, A., and Gospodarowicz, D. Ann N.Y. Acad. Sci. 638: 1, 1991; Eckenstein, F. P., J.Neurobiology 25: 1467, 1994; Mason, I.J. Cell 78: 547, 1994). As of December 1994, nine members of this family had been characterized by molecular cloning. The first two members of the family to be characterized, acidic fibroblast growth factor (aFGF/FGF-1) and basic fibroblast growth factor (bFGF/FGF-2), have been found in numerous tissues, including for example brain, eye, kidney, placenta, and adrenal (Jaye et al., Science 233: 541, 1986; Abraham et al., Science 233: 545, 1986). These factors have been shown to be potent mitogens and survival factors for a variety of mesoderm and neurectoderm-derived tissues, including fibroblasts, endothelial cells, hippocampal and cerebral cortical neurons, and astroglia (Burgess, W. H. and Maciag, T. Ann. Rev. Biochemistry 58: 575, 1989). Additional members of the FGF family include: int-2/FGF-3, identified as one of the frequent sites of integration of the mouse mammary tumor virus, and therefore a presumptive oncogenic factor (Smith et al., EMBO J. 7: 1013, 1988); FGF-4 (Delli-Bovi et al., Cell 50: 729, 1987) and FGF-5 (Zhan et al., Mol. Cell Biol. 8, 3487, 1988) as transforming genes in the NIH 3T3 transfection assay; FGF-6, isolated by molecular cloning based on its homology to FGF-4 (Marics et al., Oncogene 4: 335 (1989); keratinocyte growth factor/ FGF-7, identified as a mitogen for keratinocytes (Finch et al., Science 245: 752, 1989); FGF-8 as an androgen-induced mitogen for mammary carcinoma cells (Tanaka et al., Proc. Natl. Acad. Sci. USA 89: 8928, 1992); and FGF-9 as a mitogen for primary astrocytes (Miyamoto et al., Mol. Cell Biol. 13: 4251, 1993). Several of the FGFs, including aFGF and bFGF, lack a classical signal sequence; the mechanism by which they are secreted is not known.
All members of the FGF family share approximately 25% or more amino acid sequence identity, a degree of homology indicating that they are likely to share nearly identical three-dimensional structures. Support for this inference comes from a comparison of the three-dimensional structures of bFGF and interleukin 1-beta determined by x-ray diffraction (Eriksson et al., Proc. Natl. Acad. Sci USA 88: 3441, 1991; Zhang et al., Proc. Natl. Acad. Sci USA 88: 3446, 1991; Ago et al., J.Biochem. 110: 360, 1991). Although these proteins share only 10% amino acid identity, the alpha carbon backbones of the two crystal structures can be superimposed with a root-mean square deviation of less than 2 angstroms (Zhang et al., Proc. Natl. Acad. Sci USA 88: 3446, 1991). Both proteins consist almost entirely of beta-sheets, which form a barrel composed of three copies of a four-stranded beta-meander motif. The likely heparin- and receptor-binding regions are located on nearby regions on one face of the protein.
aFGF, bFGF, and FGF-7/KGF have been shown to exert some or all of their biological activity through high affinity binding to cell surface tyrosine kinase receptors (e.g., Lee, P. L. et al., Science 245: 57, 1989; reviewed in Johnson, D.E. and Williams, L.T., Adv. Cancer Res. 60: 1, 1993). Many members of the FGF family also bind tightly to heparin, and a terniary complex of heparin, FGF, and transmembrane receptor may be the biologically relevant signalling species. Thus far four different genes have been identified that encode receptors for FGF family members. Recent work has shown that receptor diversity is increased by differential mRNA splicing within the extracellular ligand binding domain, with the result that multiple receptor isoforms with different ligand binding properties can be encoded by the same gene (Johnson, D. E. and Williams, L. T., Adv. Cancer Res. 60: 1, 1993). In tissue culture systems, the binding of aFGF or bFGF to its cell surface receptor activates phospholipase C-gamma (Burgess, W. H. et al., Mol. Cell Biol. 10: 4770, 1990), a pathway known to integrate a variety of mitogenic signals.
Identification and characterization of new members of the FGF family will provide insights into the mechanisms by which cells and organs control their growth, survival, senescence, differentiation, and recovery from injury.